Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination.

Ras proteins play a central role in transducing signals that control cell proliferation, differentiation, motility, and survival. The location-specific signaling activity of Ras has been previously shown to be regulated by ubiquitination [1]. However, the molecular machinery that controls Ras ubiquitination has not been defined. Here we demonstrate through biochemical ...
and functional analyses that Rabex-5 (also known as RabGEF1) [2, 3] functions as an E3 ligase for Ras. Rabex-5-mediated Ras ubiquitination promotes Ras endosomal localization and leads to the suppression of ERK activation. Moreover, the Ras effector RIN1 [4, 5] is required for Rabex-5-dependent Ras ubiquitination, suggesting a feedback mechanism by which Ras activation can be coupled to ubiquitination. These findings define new elements in the regulatory circuitry that link Ras compartmentalization to signaling output.
Mesh Terms:
Animals, COS Cells, Cercopithecus aethiops, Endosomes, Extracellular Signal-Regulated MAP Kinases, Feedback, Physiological, Guanine Nucleotide Exchange Factors, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination, ras Proteins
Curr. Biol.
Date: Aug. 10, 2010
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